The main objective of this project is to develop a new therapeutic to improve the outcome for patients with intermediate-risk prostate cancer. The indication is a first-line adjuvant to be combined with radiation therapy for prostate cancer. The desired outcomes are improved local control rate, decreased recurrence and improved disease-free survival. This grant will enable development and evaluation of ProstAtak(tm), a product aimed at improving the outcome of prostate cancer patients, in a randomized Phase 2 clinical study. Prostate cancer is the second leading cause of cancer death in men in the US with approximately 30,000 deaths expected in 2006. Current therapies provide an excellent 5yr survival prognosis for the 230,000 new annual diagnoses. However, each year 60,000-100,000 men develop prostate cancer recurrence for which they receive surgical or pharmacologic castration, a life extending but non-curative therapy. Castration negatively impacts quality of life. Drugs that decrease recurrence of prostate cancer and do not diminish current success from standard therapies would be of great significance. ProstAtak(tm) is a biologic drug composed of an adenoviral vector with the Herpes thymidine-kinase gene (AdV-tk) formulated for prostate delivery followed by an oral antiherpetic prodrug. When combined with standard surgery or radiation, ProstAtak(tm) has been shown to generate a systemic vaccine effect through a technology termed gene mediated cytotoxic immunotherapy (GMCI(tm)). AdV-tk, the principal component of ProstAtak(tm), has an excellent safety profile with over 300 patient doses delivered in multiple Phase 1 studies, and a non-randomized Phase 2 study. Prostate cancer has shown susceptibility to ProstAtak(tm) alone, and in the context of GMCI(tm) with radiation. The purpose of this application is to support design, implementation and evaluation of a randomized Phase 2 controlled trial of ProstAtak(tm) with radiation compared to placebo with radiation in localized intermediate-risk prostate cancer. A working group of urology, radiation therapy, pathology, immunology and biostatistics experts from top academic institutions has been assembled to collaborate in the development and conduct the proposed studies. A clinical protocol from this group has been prepared. The intermediate-risk group was selected based on positive results from the non-randomized study, the potential to differentiate outcomes in this patient population, and because standard treatment for this stage provides an opportunity to easily incorporate GMCI(tm) without adding significant discomfort to the patients. The proposed trial will be the first to prospectively evaluate efficacy of AdV-tk in humans and, if successful, may lead to the first drug with early stage prostate cancer as its primary indication. A secondary objective is to prospectively evaluate surrogate end-points for early stage prostate cancer. Prostate cancer recurrence is a growing problem in the US due to earlier diagnosis and increased use of life-extending, non-curative therapies. The American Cancer Society estimates that in 2006 there will be 230,000 new cases, 60,000-100,000 recurrences, and 30,000 deaths from prostate cancer. Upon recurrence, the treatment is surgical or pharmacologic castration, which is non-curative and associated with significant morbidity. Usually by the time of death, men have been suffering from prostate cancer recurrence and the side effects of treatments for over 10 years. The costs to individuals and society of treatment, lost productivity and compromised quality of life due to recurrence are a huge problem, which needs to be addressed with new more effective and less toxic therapies. The main objective of this SBIR project is to develop a new therapeutic to improve the outcome for patients with intermediate-risk prostate cancer. This grant will enable evaluation of ProstAtak(tm), a product aimed at improving the outcome of prostate cancer patients, in a randomized Phase 2 clinical study. In addition, a secondary objective is to prospectively evaluate surrogate end-points for early stage prostate cancer. There are no approved drugs with early stage prostate cancer as their primary indication; ProstAtak(tm) would be a first. This is in part due to the prolonged natural history of the disease, which translates into prohibitory long clinical development times. The availability of validated shorter-term surrogate end-points would significantly impact the overall approach of therapy development for this disease. [unreadable] [unreadable] [unreadable]